Imeglimin confers protection against intestinal ischemia/reperfusion injury in rats through AMPK-dependent inhibition of NF-κB/NLRP3 inflammasome signaling and mitigation of oxidative stress and apoptosis

Isolinderalactone alleviates hepatic ischemia-reperfusion injury by inhibiting endoplasmic reticulum stress through the SIRT1/IRE1α signaling pathway.

BACKGROUND Hepatic ischemia-reperfusion injury (HIRI) remains a clinical challenge during liver surgery and transplantation, largely due to the lack of effective pharmacological interventions. Isolinderalactone (ILL), a sesquiterpene lactone, exhibits potent antioxidant and anti-inflammatory properties. However, its therapeutic potential for HIRI and its precise molecular targets, particularly regarding the SIRT1/IRE1α-mediated endoplasmic reticulum stress (ERS) pathway, remain to be elucidated. OBJECTIVE This study aimed to determine the hepatoprotective effects of ILL against HIRI and investigate its regulatory mechanism centered on the SIRT1/IRE1α signaling axis. METHODS HIRI was modeled in mice via ischemia/reperfusion (I/R) and in AML12 cells via hypoxia/reoxygenation (H/R). Cellular injury, oxidative stress, endoplasmic reticulum stress (ERS), apoptosis, and inflammatory responses were assessed using biochemical, histological, molecular, and cellular imaging techniques. The physical and functional interaction between ILL and SIRT1 was characterized through molecular docking, dynamics simulations, surface plasmon resonance, and enzymatic activity assays. The role of SIRT1 was further validated using genetic knockdown and pharmacological inhibition (EX527). RESULTS ILL treatment significantly attenuated liver tissue damage, restored intracellular redox homeostasis, and mitigated ERS-induced inflammation and apoptosis. Mechanistically, ILL not only upregulated SIRT1 expression but also directly bound to SIRT1 to enhance its deacetylase activity, thereby suppressing the downstream IRE1α/TRAF2/JNK signaling cascade. Notably, SIRT1 silencing or pharmacological blockade with EX527 significantly blunted, albeit did not completely abolish, the protective effects of ILL, indicating that the SIRT1/IRE1α axis serves as a primary, though not exclusive, mediator of ILL's hepatoprotective activity. CONCLUSION ILL attenuates HIRI by simultaneously elevating SIRT1 expression and activating its deacetylase function, thereby restraining IRE1α-dependent ERS and subsequent hepatic injury. These findings highlight ILL as a promising therapeutic candidate for the management of perioperative HIRI.

Kaempferol alleviates myocardial ischemia-reperfusion injury by activating the Nrf2/GPX4 signaling pathway to inhibit ferroptosis.

Myocardial ischemia-reperfusion injury (MIRI) remains a major cause of myocardial dysfunction after reperfusion therapy, and effective pharmacological interventions are still limited. Ferroptosis plays a pivotal role in MIRI pathogenesis. This study investigated whether kaempferol, a natural flavonoid, protects against MIRI by activating nuclear factor erythroid 2-related factor 2 (Nrf2)/glutathione peroxidase 4 (GPX4)-mediated ferroptosis defense. In male C57BL/6 mice subjected to left anterior descending coronary artery ligation/reperfusion, kaempferol reduced myocardial infarct size, preserved cardiac contractile function, decreased serum cardiac injury markers, and attenuated myocardial fibrosis and apoptosis. In H9c2 cardiomyocytes exposed to hypoxia/reoxygenation (HR), kaempferol improved cell viability and reduced the expression of cleaved caspase-3 and cleaved PARP. Mechanistically, kaempferol restored antioxidant capacity, alleviated lipid peroxidation and iron overload, and preserved mitochondrial membrane potential. Non-targeted metabolomics revealed that kaempferol modulated glutamate/glutamine metabolism, glycerophospholipid metabolism, and glutathione-related pathways. Furthermore, kaempferol was able to reverse MIRI/HR-induced suppression of Nrf2, solute carrier family 7 member 11 (SLC7A11), and GPX4, inhibit RAS-selective lethal 3 (RSL3)-induced ferroptosis, and increase phosphorylation of Nrf2 at Ser40. Molecular docking analysis suggested that kaempferol may interact with the Nrf2-binding pocket of its repressor protein, implying a potential upstream mechanism for Nrf2 activation. Importantly, the Nrf2 inhibitor ML385 markedly weakened the protective and anti-ferroptotic effects of kaempferol. Collectively, these findings demonstrate that kaempferol ameliorates MIRI by activating Nrf2/GPX4-related antioxidant signaling, thereby inhibiting ferroptosis, attenuating apoptosis, reducing myocardial structural damage, and ultimately preserving cardiac function.

Vinpocetine attenuates myocardial ischemia/reperfusion injury in mice by suppressing oxidative stress, inflammation, and apoptosis.

Gomisin A Attenuates Cerebral Ischemia/Reperfusion Injury Through Activation of the VEGF/PI3K/AKT/NOS3 Signaling Pathway.

Ameliorative Effects of Silymarin on Ovarian Ischemia/Reperfusion Injury via Modulation of Oxidative Stress and Inflammatory Pathways

Ischemia/reperfusion (IR) injury secondary to ovarian torsion results in oxidative stress, inflammation, and structural damage to the ovary. Silymarin (SLY), a natural flavonoid complex, possesses potent antioxidant and anti‐inflammatory effects. The present study was designed to evaluate the protective effects of SLY on ovarian IR injury. An experimental model of OIR was created, and animals were divided into Sham, OIR, and OIR + SLY groups. An acute single dose of silymarin (100 mg/kg) was given to the treatment group. Tissue and serum levels of TNF‐α, IL‐17, TGF‐β1, and H2O2 were determined, as well as TOS. Tissue oxidative stress parameters MDA, GSH content, and SOD activity were assessed. Histopathological evaluation of ovarian tissues was done. Compared to sham controls, the OIR group exhibited significantly higher tissue and serum inflammatory cytokine levels, and oxidative stress indicators, as well as higher MDA levels and lower GSH and SOD activity (p < 0.05). Histological analysis revealed significant vascular congestion, bleeding, and tissue deterioration. SLY therapy significantly decreased inflammatory cytokines and lipid peroxidation while increasing antioxidant defenses (p < 0.05). Histopathological results also showed improved ovarian tissue integrity in the treatment group. SLY may be used as an adjuvant treatment for ovarian torsion, as it reduces oxidative stress and inflammation in OIR injury of the ovary while preserving its histological structure.

Protective effects of chlorogenic acid against LPS-induced intestinal oxidative injury in mice via activation of the PI3K/Akt-Nrf2/HO-1 signaling axis

Introduction Oxidative stress is a key pathological cause of intestinal epithelial injury and related intestinal diseases. Chlorogenic acid (CGA), a natural polyphenol, has notable antioxidant activity. This study explored the multi-target protective effects of CGA on intestinal epithelial cells and mouse intestinal tissue against oxidative injury, as well as its underlying molecular mechanisms. Methods Network pharmacology was applied to screen core targets and enriched pathways of CGA against oxidative stress. H₂O₂-induced MODE-K cell oxidative damage model and LPS-induced mouse intestinal injury model were constructed. CCK-8, biochemical detection, qPCR, molecular docking, Western blotting and histopathological assay were performed to verify the protective effects and related signaling pathways. Results Network pharmacology predicted PI3K/Akt and Nrf2/HO-1 pathways as crucial targets. In vitro, CGA elevated cell viability, reduced oxidative injury markers, upregulated antioxidant factors, and regulated apoptosis-related proteins. CGA blocked Keap1-Nrf2 binding, activated Nrf2/HO-1 and promoted Akt phosphorylation. In vivo, CGA alleviated LPS-induced intestinal pathological injury, while PI3K inhibitor LY294002 reversed its protective effects, confirming the critical role of PI3K/Akt-Nrf2/HO-1 axis. Conclusion CGA exerts multi-target antioxidant and intestinal protective effects by inhibiting Keap1-Nrf2 interaction and activating PI3K/Akt-Nrf2/HO-1 signaling axis, mitigating intestinal oxidative injury. Our findings provide a mechanistic basis for the application of CGA as a functional food ingredient or dietary intervention to alleviate intestinal oxidative stress in livestock.